Epithelial cells often require polarization in two axes for their function, ubiquitous apical-basal polarity and a second axis within the plane of the epithelium, called Planar Cell Polarity (PCP). Typical mammalian PCP examples are highlighted by the organization of the skin and many internal organs, e.g. the inner ear with its sensory cilia and, importantly, also include directed cell migration during mammalian gastrulation and neural tube closure. In Drosophila, all adult cuticular structures show PCP features. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination in development and disease. PCP is coordinated by the activity of the Frizzled (Fz) receptor (with Wnt family members as their ligands) and it's associated signaling cascade (Fz/PCP signaling), which is highly conserved throughout evolution and regulates many aspects of coordinated cellular polarization, including directed cell migration. Although the frame work of the signaling pathway(s) regulating PCP is beginning to be established, the specific links between PCP-signaling and the resulting cellular responses, including the regulation of cell adhesion and cell motility are only beginning to be dissected. Similarly, the cell adhesion effectors of the PCP pathway(s) are largely unknown. The scope of this application is to dissect the mechanistic regulatory interactions between PCP associated signaling pathways and the respective cell adhesion factors, using the Drosophila eye paradigm as a model. Based on our preliminary studies we hypothesize that regulatory input from Fz/PCP, Notch and receptor tyrosine kinase (RTK)/Ras signaling converges on E-cadherin/catenin, Nectin/Afadin, and Integrin/ECM mediated cell adhesion/cell motility regulation. Strikingly, all signaling pathways involved (Wnt/Fz-PCP, Notch and RTK/Ras-signaling) employ a non-canonical pathway branch. The components of these cell adhesion specific signaling branches are only being discovered now, and thus an exciting new signaling network is emerging. We will use a combination of Drosophila in vivo studies, live imaging in the fly eye, and biochemical experiments to define the mechanistic regulatory interactions between the signaling components and the cell adhesion factors, leading to a highly regulated cell motility process. Several components of the signaling pathways and cell adhesion modules are critically linked to cancer and other diseases, and are also associated with stem cell biology. Thus the information acquired in this application will not only advance our understanding of regulated cellular motility but will also be of medical relevance in several disease associated contexts. PUBLIC HEALTH RELEVANCE: Wnt/Fz-planar cell polarity, RTK/Ras, and Notch signaling pathways are implicated in many developmental patterning contexts and also linked to several congenital diseases, ranging from hearing defects to cancer. This application addresses the mechanistic regulatory inputs of these signaling pathways to cell adhesion molecules specific to directed cell motility, cell polarity, and associated organ morphogenesis. The information acquired here will be of importance for our molecular understanding of organogenesis and several medical disorders.